The invention is directed to a process for preparing isatins and to novel compounds produced therein, and is particularly directed to a process in which isatins can be prepared from anilines with a wide variety of substituents.
Isatins have long been considered as valuable synthetic intermediates in the preparation of both pharmaceuticals and dyes. See, for example, the chapter on Indigoid Dyes, pp. 551-576, The Chemistry of Synthetic Dyes, Reinhold Publishing Co., New York, N.Y. (1955). As a consequence, considerable effort has been devoted to developing useful synthetic approaches to the preparation of this class of compounds from readily available starting materials, particularly the anilines. Unfortunately, the processes heretofore available were limited in regard to the type of substituents which could be present in the starting anilines due to the fact that such processes required catalysis by strong acids. Thus, Sandmeyer, Helv. Chim. Acta, 2, 234 (1919) discloses a process in which aniline is reacted with trichloroacetaldehyde and then with hydroxylamine in base. The resulting isonitrosoacetanilide is then heated in sulfuric acid. Also, Stolle, J. Prakt. Chem., 105, 137 (1922) discloses a process in which an aniline is treated with oxalyl chloride followed by Friedel-Crafts type acylation in the presence of a strong Lewis acid. Since both methods require electrophilic attack on the aromatic ring, the presence of strong electron-withdrawing groups in the aniline, especially in the meta position, tend to inhibit the reaction. For example, a nitro group in the meta position effectively blocks these syntheses.
A new method for the general synthesis of isatins was recently described by P. G. Gassman, et al., J. Org. Chem., 42, 1344 (1977). The process involves the chlorination of 3-lower hydrocarbonthiooxindoles, readily available from anilines, followed by hydrolysis, and has the advantage that the starting 3-lower hydrocarbonthiooxindoles can readily be prepared from anilines having a broad spectrum of electron-withdrawing and electron-donating substituents. It has the disadvantage, however, that mercuric oxide and boron trifluoride-etherate are used in the hydrolysis and consequently involves the usual problems attending the large scale use of these reagents.